Novel biologic markers of treatment resistance in locally advanced cervical carcinoma Cervical cancer is the third leading cause of cancer mortality in women worldwide, despite effective cytologic screening programs and the ability to treat pre-invasive cervical dysplasia. While approximately two-thirds of women will be diagnosed when their disease is confined to the cervix and will potentially be cured with surgery, the remaining one-third will have cancer that has spread beyond the cervix into the surrounding pelvic tissues (known as locally advanced cervical cancer). The main treatment modality for these patients is platinum (Pt) chemotherapy in combination with pelvic radiation therapy (CRT). Unfortunately, tumor recurrence rates at five years still range from 30-40%. A small percentage of these patients with recurrence following combined CRT can be salvaged with ultra-radical surgery, but for the majority of these women palliative chemotherapy is the only remaining option. High failure rates after radiation and Pt-based therapy provide a compelling rationale for the identification of molecular markers associated with resistance. Validation of such markers would make it possible to identify those patients who are likely to fail standard therapy, leading the clinician to pursue alternative non-Pt based regimens such as targeted therapies, biologics and clinical trials. Our overall hypothesis is that both tumor and normal tissue cells contribute to local changes that affect tumor growth and resistance to combined CRT. We predict that changes in the vascular endothelial cells that occur duing angiogenesis will provide novel biomarkers that will be prognostic for treatment success. Further, distinct tumor proteins also represent biomarkers that are prognostic for tumor response to CRT. Thus our research program aims to identify and validate endothelial-derived proteins involved in angiogenesis, as well as tumor- specific DNA repair proteins as novel biomarkers to predict tumor resistance to primary CRT. Our third aim is to combine these markers with standard clinical and pathologic prognostic and diagnostic parameters to develop a composite index that is predictive of tumor response to therapy and patient outcome. PUBLIC HEALTH RELEVANCE: Cervical cancer is the third leading cause of cancer mortality in women worldwide, despite effective cytologic screening programs and the ability to successfully treat pre-invasive cervical dysplasia. This research program aims to develop a composite biomarker and clinicopathologic index that is predictive of tumor persistence or durable response to cisplatin-based chemoradiation, in order to improve clinical decision-making for women with cervical carcinoma.